Stroke is a leading cause of death and a major source of disability and suffering. Alzheimer' s disease is the most frequent cause of dementia in the elderly, affecting an estimated four million people in the US alone. Apolipoprotein E has been identified as a modulator or a susceptibility gene in both these diseases. Of the three common Apo E isoforms, Apo E4 is associated with poor outcome after stroke, traumatic brain injury, intracerebral hemorrhages, and is a major risk factor for Alzheimer's disease and possibly vascular dementia. In contrast, Apo E3 and Apo E2 isoforms are protective and associated with lower risk for these diseases. Similar observations were made in Apo E transgenic mice. The long-term objective of this study is to elucidate the molecular mechanism by which Apo E exerts these isoform-specific effects in the brain and specifically how Apo E3 is neuroprotective. The preliminary results show that Apo E3 and to a lesser extent Apo E4 stimulates the synthesis of a neuroprotective protease inhibitor, plasminogen activator inhibitor 1 (PAI-1) in vitro and that PAI-1 protects mice against different forms of neurodegeneration most likely by inhibiting serine protease tissue plasminogen activator (tPA). TPA is probably the most abundant protease in the brain and it cause neurodegeneration in mice and possibly humans. Therefore, the investigators hypothesize that Apo E3 activates a signaling pathway that leads to the production of PAI-1, which then protects neurons against injury, whereas Apo E4 induces less PAI-1 and does not protect efficiently against neurodegeneration. The proposed studies are designed to assess this novel function of Apo E in brain injury and neuroprotection. In Specific Aim #1, how Apo E induces PAI-1 will be determined at the molecular level. In Aim #2, apo E induction of PAI-1 and its influence on neurotoxicity will be examined in cell cultures. In Aim #3, the neuroprotective effect of Apo E will be assessed in vivo. These results may help devise novel therapeutic strategies to mimic the beneficial Apo E3 effects or inhibit the detrimental Apo E4 effects in brain injury and neurodegeneration.